Yu Chen1, Li Xing1, William J. Welsh1, Weida Tong2, Roger Perkins2, and Daniel Sheehan3

A QSAR Study of the Binding of Suspected Endocrine Disrupting Compounds (EDCs) to the Estrogen Receptor

1Department of Chemistry & Center for Molecular Electronics, University of Missouri-St. Louis, St. Louis, MO 63121, USA.
2R.O.W. Sciences, Inc., Jefferson, AR, 72079, USA.
3National Center for Toxicological Research (NCTR), Jefferson, AR 72079, USA.

The recent cloning of the estrogen receptor (ER) subtype suggests that the selective effects of certain estrogenic compounds (e.g., tamoxifen) arises from control of different subsets of estrogen-responsive promoters by the two ER subtypes, and . In order to identify the similarity/dissimilarity between these two ER subtypes in terms of ligand recognition and binding, separate 3D-QSAR models were developed for both the and . ER based on Relative Binding Affinity (RBA) data for a diverse training set of 31 estrogenic compounds. Both 3D-QSAR models, which correlated the observed RBA values for the training-set compounds with their calculated 3D steric and electrostatic fields, exhibited excellent self-consistency (r2 = 0.99) and predictive ability (q2 > 0.65). Values of RBA predicted by these 3D-QSAR models for a test set of compounds (i.e., not used to construct the models) exhibited excellent agreement with experimental data. Inspection of the corresponding CoMFA contour maps for and . ER suggests subtle differences in their steric and electrostatic requirements for ligand binding.

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